Rheumatoid Arthritis: Gabriel SE

Gabriel SE. · No affiliation provided · Arthritis Rheum. · Pubmed #18311805 links to  free full text

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Davis JM, Maradit-Kremers H, Gabriel SE. · No affiliation provided · J Rheumatol. · Pubmed #16206334 links to  free full text

This publication has no abstract.

Doran MF, Gabriel SE. · No affiliation provided · J Rheumatol. · Pubmed #11550957 links to  free full text

This publication has no abstract.

Gabriel SE. · Department of Health Sciences Research, Mayo Foundation, Rochester, MN 55905, USA. · Ann Rheum Dis. · Pubmed #19022810 No free full text.

Abstract: Premature death has been long recognised as a manifestation of rheumatoid arthritis (RA). Three lines of evidence can explain why patients with RA die prematurely and why the mortality gap between patients with RA and the general population appears to widening. First, patients with RA have a higher risk of several serious comorbid conditions and they tend to experience worse outcomes after the occurrence of these illnesses. Second, patients with RA do not appear to receive optimal primary or secondary preventive care. And third, the systemic inflammation and immune dysfunction associated with RA appears to promote and accelerate comorbidity and mortality. This paper provides a brief summary and interpretation of the data underlying these findings. Together, these results provide a compelling argument in favour of a focused research programme aimed specifically at eliminating premature death in patients with RA.

Gabriel SE. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA. · Am J Med. · Pubmed #18926169 No free full text.

Abstract: Patients with rheumatoid arthritis (RA) are at increased risk of mortality compared with the general population. Evidence suggests that this increased mortality can largely be attributed to increased cardiovascular (CV) death. In a retrospective study of an inception cohort of RA patients in Rochester, MN, we found that patients with RA were at increased risk of CV death, ischemic heart disease, and heart failure compared with age- and sex-matched community controls. In addition, when we examined coronary artery tissue from autopsied RA patients, we observed increased evidence of inflammation and an increased proportion of unstable plaques. We also investigated the contribution of traditional and RA-specific risk factors to this increased risk of CV morbidity and mortality. Although traditional CV disease risk factors were found to contribute to the increased risk of mortality in RA patients, they did not fully explain the increased CV mortality observed in RA. Instead, increased inflammation associated with RA appears to contribute substantially to the increased CV mortality. Together with other studies that have demonstrated similar associations between RA and CV mortality, these data suggest that more aggressive management of inflammation in RA may lead to significant improvements in outcomes for patients with RA.

Kremers HM, McEvoy MT, Dann FJ, Gabriel SE. · Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. · J Am Acad Dermatol. · Pubmed #17433490 No free full text.

Abstract: Psoriasis has been traditionally viewed as an inflammatory skin disorder of unknown origin. Recent advances in the immunopathogenesis and genetics of psoriasis have broadened our understanding of psoriasis. Psoriasis is now considered a systemic inflammatory condition analogous to other inflammatory immune disorders. Patients with other immune disorders, such as systemic lupus erythematosus or rheumatoid arthritis, are known to be at increased risk of heart disease. Similarly, patients with psoriasis may carry an excess risk of heart disease, which would represent an important previously unrecognized cause of morbidity and mortality. This review summarizes the current evidence for an increased cardiovascular risk in patients with psoriasis and outlines deficits in our knowledge in this area.

Kremers HM, Gabriel SE. · Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. · Curr Heart Fail Rep. · Pubmed #16928338 No free full text.

Abstract: The risk of cardiovascular disease is increased in patients with rheumatoid arthritis (RA). Although the pathogenesis of cardiovascular disease in patients with RA is largely unknown, evidence to date indicates that it involves complex interactions between the traditional and nontraditional cardiovascular risk factors as well as various medications commonly used for the treatment of RA patients. This review provides an overview of the clinical studies that demonstrate increased risk of coronary heart disease and heart failure in patients with RA and also discusses the potential role of the various risk factors.

Maradit-Kremers H, Crowson CS, Nicola PJ, Ballman KV, Roger VL, Jacobsen SJ, Gabriel SE. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Arthritis Rheum. · Pubmed #15693010 links to  free full text

Abstract: OBJECTIVE: To examine the risk of clinical coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) compared with age- and sex-matched non-RA subjects, and to determine whether RA is a risk factor for CHD after accounting for traditional CHD risk factors. METHODS: We assembled a population-based incidence cohort of 603 Rochester, Minnesota residents ages >or=18 years who first fulfilled the American College of Rheumatology (ACR) 1987 criteria for RA between January 1, 1955 and January 1, 1995, and 603 age- and sex-matched non-RA subjects. All subjects were followed up through their complete inpatient and outpatient medical records, beginning at age 18 years until death, migration, or January 1, 2001. Data were collected on CHD events and traditional CHD risk factors (diabetes mellitus, hypertension, dyslipidemia, body mass index, smoking) using established diagnostic criteria. CHD events included hospitalized myocardial infarction (MI), unrecognized MI, coronary revascularization procedures, angina pectoris, and sudden CHD deaths. Conditional logistic regression and Cox regression models were used to estimate the risk of CHD associated with RA, both prior to and following RA diagnosis, after adjusting for CHD risk factors. RESULTS: During the 2-year period immediately prior to fulfillment of the ACR criteria, RA patients were significantly more likely to have been hospitalized for acute MI (odds ratio [OR] 3.17, 95% confidence interval [95% CI] 1.16-8.68) or to have experienced unrecognized MIs (OR 5.86, 95% CI 1.29-26.64), and less likely to have a history of angina pectoris (OR 0.58, 95% CI 0.34-0.99) compared with non-RA subjects. After the RA incidence date, RA patients were twice as likely to experience unrecognized MIs (hazard ratio [HR] 2.13, 95% CI 1.13-4.03) and sudden deaths (HR 1.94, 95% CI 1.06-3.55) and less likely to undergo coronary artery bypass grafting (HR 0.36, 95% CI 0.16-0.80) compared with non-RA subjects. Adjustment for the CHD risk factors did not substantially change the risk estimates. CONCLUSION: Patients with RA have a significantly higher risk of CHD when compared with non-RA subjects. RA patients are less likely to report symptoms of angina and more likely to experience unrecognized MI and sudden cardiac death. The risk of CHD in RA patients precedes the ACR criteria-based diagnosis of RA, and the risk cannot be explained by an increased incidence of traditional CHD risk factors in RA patients.

Gabriel SE, Coyle D, Moreland LW. · Health Sciences Research, Mayo Foundation, Rochester, Minnesota 55905, USA. · Pharmacoeconomics. · Pubmed #11548909 No free full text.

Abstract: Rheumatoid arthritis is one of the most common chronic systemic inflammatory diseases, affecting approximately 1% of the adult population. Disease-modifying antirheumatic drugs (DMARDs) have been the mainstay of treatment for rheumatoid arthritis when combined with physical therapy and aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs. Recently, a number of new biological therapies have been introduced for the treatment of this condition and will have a major impact on the future management of this disabling disease. In this review, we summarise data on the efficacy and tolerability of the currently available DMARDs, including gold compounds, antimalarials, penicillamine, cytotoxic drugs (azathioprine and cyclophosphamide), sulfasalazine, methotrexate, leflunomide, cyclosporin, anti-tumour necrosis factor agents, combination therapy and apheresis. A literature review and quality assessment of economic evaluations of DMARDs is presented, illustrating that there has been a paucity of economic evaluations on these agents and showing the variable quality of those studies that are available. The manuscript also addresses the pharmacoeconomic implications of the new agents for rheumatoid arthritis; the need for formal long term economic evaluations in order to determine the cost effectiveness of these costly, but highly effective, new treatments is emphasised.

Gabriel SE. · Departments of Health Sciences Research and Internal Medicine, Division of Rheumatology, Mayo Foundation, Rochester, Minnesota, USA. · Rheum Dis Clin North Am. · Pubmed #11396092 No free full text.

Abstract: Studies of the descriptive epidemiology of RA indicate a population prevalence of 0.5% to 1% and a highly variable annual incidence (12-1200 per 100,000 population) depending on gender, race/ethnicity, and calendar year. Secular trends in RA incidence over time have been shown in several studies, supporting the hypothesis of a host-environment interaction. People with RA have a significantly increased risk of death compared with age- and sex-matched controls without RA from the same community. The determinants of this excess mortality remain unclear; however, reports suggest increased risk from gastrointestinal, respiratory, cardiovascular, infectious, and hematologic diseases among RA patients compared with controls. Despite extensive epidemiologic research, the etiology of RA is unknown. Several risk factors have been suggested as important in the development or progression of RA. These include genetics, infectious agents, oral contraceptives, smoking, and formal education. Epidemiologic research is an essential contributor to our understanding of RA.

Gabriel SE, Michaud K. · Department of Health Sciences Research, Mayo Foundation, Rochester, MN 55905, USA. · Arthritis Res Ther. · Pubmed #19519924 links to  free full text

Abstract: Epidemiology is the study of the distribution and determinants of disease in human populations. Over the past decade there has been considerable progress in our understanding of the fundamental descriptive epidemiology (levels of disease frequency: incidence and prevalence, comorbidity, mortality, trends over time, geographic distributions, and clinical characteristics) of the rheumatic diseases. This progress is reviewed for the following major rheumatic diseases: rheumatoid arthritis (RA), juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, giant cell arteritis, polymyalgia rheumatica, gout, Sjögren's syndrome, and ankylosing spondylitis. These findings demonstrate the dynamic nature of the incidence and prevalence of these conditions--a reflection of the impact of genetic and environmental factors. The past decade has also brought new insights regarding the comorbidity associated with rheumatic diseases. Strong evidence now shows that persons with RA are at a high risk for developing several comorbid disorders, that these conditions may have atypical features and thus may be difficult to diagnose, and that persons with RA experience poorer outcomes after comorbidity compared with the general population. Taken together, these findings underscore the complexity of the rheumatic diseases and highlight the key role of epidemiological research in understanding these intriguing conditions.

Icen M, Nicola PJ, Maradit-Kremers H, Crowson CS, Therneau TM, Matteson EL, Gabriel SE. · Department of Health Sciences Research, Mayo Foundation, 200 First St. SW, Rochester, MN 55905, USA. · J Rheumatol. · Pubmed #19004043 No free full text.

Abstract: OBJECTIVE: Features of systemic lupus erythematosus (SLE) are commonly observed in patients with rheumatoid arthritis (RA). However, their frequency and clinical significance are uncertain. We examined the frequency of SLE features in RA and their effect on overall mortality. METHODS: We assembled a population-based incidence cohort of subjects aged >or=18 years first diagnosed with RA [1987 American College of Rheumatology (ACR) criteria] between 1955 and 1995. Information regarding disease characteristics, therapy, comorbidities, and SLE features (1982 ACR criteria) were collected from the complete inpatient and outpatient medical records. Cox regression models were used to estimate the mortality risk associated with lupus features. RESULTS: The study population comprised 603 subjects with incident RA (mean age 58 yrs, 73% women) with a mean followup time of 15 years. By 25 years after RA incidence, >or=4 SLE features were observed in 15.5% of the subjects with RA. After adjustment for age and sex, occurrence of >or=4 SLE features was associated with increased overall mortality [hazard ratio (HR) 5.54, 95% confidence interval (CI) 3.59-8.53].With further adjustment for RA characteristics, therapy, and comorbidities, the association weakened but remained statistically significant (HR 2.56, 95% CI 1.60-4.08). After adjustment for age, sex, RA characteristics, therapy, and comorbidities, thrombocytopenia (2.0, 95% CI 1.2, 3.1) and proteinuria (1.8, 95% CI 1.3, 2.6) were significantly associated with mortality. CONCLUSION: SLE features were common in RA, given sufficient observation time. Subjects with RA who developed >or=4 SLE features had an increased risk of death. Proteinuria and thrombocytopenia were individually associated with an increased mortality risk.

Davis JM, Roger VL, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. · Mayo Clinic, Rochester, Minnesota. · Arthritis Rheum. · Pubmed #18759286 No free full text.

Abstract: OBJECTIVE: To compare the clinical presentation, management, and outcome of heart failure in patients with rheumatoid arthritis (RA) compared with non-RA patients. METHODS: We conducted a community-based cohort study in the setting of Olmsted County, Minnesota, from 1979 to 2000. One hundred three patients with RA and 852 non-RA patients with incident heart failure (physician diagnosed and Framingham criteria validated) were compared. Age- and sex-adjusted rates/frequencies and multivariable logistic regression models were used to compare the clinical features and mortality of heart failure following its onset in the 2 groups of patients. RESULTS: The patients with RA were more often female and less frequently were obese, were hypertensive, or had ischemic heart disease. Patients with RA and heart failure had fewer typical symptoms and signs and were less likely to undergo echocardiography compared with non-RA patients. After adjusting for differences, the patients with RA and heart failure were more likely to have preserved ejection fraction (>/=50%). Mortality at 1 year following heart failure was higher in patients with RA compared with non-RA patients (35% versus 19%; multivariable hazard ratio 1.89, 95% confidence interval 1.26-2.84). CONCLUSION: Both the clinical presentation and the outcome of heart failure differ significantly between patients with and those without RA from the same population. Among patients with RA, the presentation of heart failure is more subtle, myocardial function is more likely preserved, while mortality from heart failure is significantly higher. These findings emphasize the importance of more vigilant screening of patients with RA for early signs of heart failure and may represent important insights into the biologic mechanisms underlying heart failure in RA.

Kremers HM, Crowson CS, Therneau TM, Roger VL, Gabriel SE. · Mayo Clinic, Rochester, MN 55905, USA. · Arthritis Rheum. · Pubmed #18668561 links to  free full text

Abstract: OBJECTIVE: To estimate the 10-year absolute risk of cardiovascular (CV) events in newly diagnosed rheumatoid arthritis (RA) patients and the potential contribution of CV risk factors to absolute risk assessment. METHODS: A population-based incidence cohort of RA patients (defined according to the American College of Rheumatology 1987 criteria) was assembled and compared with an age- and sex-matched non-RA cohort. Data were collected on CV risk factors and CV events. Cox regression models were used to estimate the 10-year risk of a combined CV end point, adjusting for CV risk factors. Subjects were classified into 5 risk categories based on their 10-year absolute risk. RESULTS: The absolute CV risk in RA patients was similar to that in non-RA subjects who were 5-10 years older. The absolute risk varied substantially according to the presence of CV risk factors. The 10-year absolute CV risk among 60-69-year-old RA patients with no risk factors was 16.8%, but rose to 60.4% if risk factors such as smoking, hypertension, dyslipidemia, diabetes, and obesity were present. Among RA patients with a low body mass index, in addition to the above risk factors, the 10-year absolute CV risk rose to 86.2%. CONCLUSION: More than half of the newly diagnosed RA patients who were 50-59 years of age and all of those >60 years of age had a >10% risk of CV disease within 10 years of their RA incidence and should be targeted for specific CV risk reduction strategies tailored to their personal risk profiles.

Gonzalez A, Icen M, Kremers HM, Crowson CS, Davis JM, Therneau TM, Roger VL, Gabriel SE. · Department of Internal Medicine, Caritas St. Elizabeth's Medical Center, Boston, Massachusetts, USA. · J Rheumatol. · Pubmed #18412312 No free full text.

Abstract: OBJECTIVE: We previously demonstrated a widening in the mortality gap between subjects with rheumatoid arthritis (RA) and the general population. We examined the contribution of rheumatoid factor (RF) positivity on overall mortality trends and cause-specific mortality. METHODS: A population-based RA incidence cohort (1955-1995, and aged >or= 18 yrs) was followed longitudinally until death or January 1, 2006. The underlying cause of death as coded from national mortality statistics and grouped according to ICD-9/10 chapters was used to define cause-specific mortality. Expected cause-specific mortality rates were estimated by applying the age-, sex-, and calendar-year-specific mortality rates from the general population to the RA cohort. Poisson regression was used to model the observed overall and cause-specific mortality rates according to RF status, accounting for age, sex, disease duration, and calendar year. RESULTS: A cohort of 603 subjects (73% female; mean age 58 yrs) with RA was followed for a mean of 16 years, during which 398 died. Estimated survival at 30 years after RA incidence was 26.0% in RF+ RA subjects compared to 36.0% expected (p < 0.001), while in RF- RA subjects, estimated survival was 29.1% compared to 28.3% expected (p = 0.9). The difference between the observed and the expected mortality in the RF+ RA subjects increased over time, resulting in a widening of the mortality gap, while among RF- RA subjects, observed mortality was very similar to the expected mortality over the entire time period. Among RF+ RA subjects, cause-specific mortality was higher than expected for cardiovascular [relative risk (RR) 1.50; 95% confidence interval (CI) 1.22, 1.83] and respiratory diseases [RR 3.49; 95% CI 2.51, 4.72]. Among RF- RA subjects, no significant differences were found between observed and expected cause-specific mortality. CONCLUSION: The widening in the mortality gap between RA subjects and the general population is confined to RF+ RA subjects and largely driven by cardiovascular and respiratory deaths.

Gonzalez A, Maradit Kremers H, Crowson CS, Nicola PJ, Davis JM, Therneau TM, Roger VL, Gabriel SE. · Mayo Clinic, Rochester, Minnesota, USA. · Arthritis Rheum. · Pubmed #17968923 links to  free full text

Abstract: OBJECTIVE: Overall mortality rates in the general US population have declined substantially over the last 4-5 decades, but it is unclear whether patients with rheumatoid arthritis (RA) have experienced the same improvements in survival. The purpose of this study was to determine the mortality trends among RA patients compared with those in the general population. METHODS: A population-based incidence cohort of RA patients was assembled, comprising all residents of Rochester, Minnesota ages > or = 18 years in whom RA was first diagnosed (according to the American College of Rheumatology [formerly, the American Rheumatism Association] 1987 criteria) between 1955 and 1995 and all residents of Olmsted County, Minnesota in whom RA was first diagnosed between 1995 and 2000. The patients were followed up longitudinally through their complete (inpatient and outpatient) medical records until death or January 1, 2007. Expected mortality was estimated from the National Center for Health Statistics life tables on the white population in Minnesota, using person-year methods. Poisson regression was used to model the observed mortality rates, adjusting for age, sex, and disease duration. RESULTS: A cohort of 822 RA patients (72% women, mean age at RA incidence 58 years) was followed up for a median of 11.7 years, during which 445 of the RA patients died. Between 1965 and 2005, the mortality rates across the calendar years for female and male RA patients were relatively constant at 2.4 and 2.5 per 100 person-years, respectively. In contrast, the expected mortality rate in the Minnesota white population decreased substantially over the same time period in both sexes. Mortality in the female general population declined from 1.0 per 100 person-years in 1965 to 0.2 per 100 person-years in 2000. Mortality in the male general population decreased from 1.2 per 100 person-years in 1965 to 0.3 per 100 person-years in 2000. Therefore, the difference between the observed and expected mortality rates increased in more recent years, resulting in a widening of the mortality gap. CONCLUSION: Our findings show that RA patients have not experienced improvements in survival over the past 4 decades, despite dramatic improvements in the overall rates of mortality in the general US population. Further research into the causes of the widening gap in mortality between RA patients and the general population, and the influence of current therapeutic strategies on mortality, is needed in order to develop strategies to reduce the excess mortality observed in RA patients.

Gonzalez A, Maradit Kremers H, Crowson CS, Ballman KV, Roger VL, Jacobsen SJ, O'Fallon WM, Gabriel SE. · Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Ann Rheum Dis. · Pubmed #17517756 No free full text.

Abstract: OBJECTIVE: To compare the frequency of traditional cardiovascular (CV) risk factors in rheumatoid arthritis (RA) compared to non-RA subjects, and examine their impact on the risk of developing selected CV events (myocardial infarction (MI), heart failure (HF) and CV death) in these two groups. METHODS: We examined a population-based incidence cohort of subjects with RA (defined according to the 1987 American College of Rheumatology criteria), and an age- and sex-matched non-RA cohort. All subjects were followed longitudinally through their complete community medical records, until death, migration, or 1 January 2001. Clinical CV risk factors and outcomes were defined using validated criteria. The chi2 test was used to compare the frequency of each CV risk factor at baseline. Person-years methods were used to estimate the rate of occurrence of each CV risk factor during follow-up. Cox models were used to examine the influence of CV risk factors on the development of CV outcomes. RESULTS: A total of 603 RA and 603 non-RA subjects (73% female; mean age 58 years) were followed for a mean of 15 and 17 years (total: 8842 and 10,101 person-years), respectively. At baseline, RA subjects were significantly more likely to be former or current smokers when compared to non-RA subjects (p<0.001). Male gender, smoking, and personal cardiac history had weaker associations with CV events among RA subjects, compared to non-RA subjects. There was no significant difference between RA and non-RA subjects in the risk imparted with respect to the other CV risk factors (ie, family cardiac history, hypertension, dyslipidaemia, body mass index, or diabetes mellitus). CONCLUSION: While some traditional CV risk factors imparted similar risk among RA compared with non-RA subjects, others (ie, male gender, smoking and personal cardiac history) imparted significantly less risk for the development of CV disease. These differences in the overall impact of traditional CV risk factors suggest that strategies to prevent CV disease and mortality focused solely on controlling traditional CV risk factors may be relatively less beneficial in RA subjects than in the general population. Further research is needed to determine optimal approaches to reducing CV morbidity and mortality in persons with RA.

Aubry MC, Maradit-Kremers H, Reinalda MS, Crowson CS, Edwards WD, Gabriel SE. · Divisions of Anatomic Pathology, Health Science Research, Biostatistics, and Rheumatology, Mayo Clinic, Rochester, Minnesota 55905, USA. · J Rheumatol. · Pubmed #17361987 No free full text.

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular diseases (CVD). We compared the histologic features of coronary artery disease in patients with RA and non-RA controls. METHODS: Forty-one RA patients who died and underwent autopsy between 1985 and 2003 were matched to 82 non-RA controls of the same age and sex with similar history of CVD and autopsy date. Coronary arteries were submitted for histologic evaluation. The grade of stenosis was evaluated in each artery. The numbers of vulnerable plaques and acute coronary lesions were counted. The composition of a representative stable and vulnerable plaque from each vessel was evaluated. Chi-square tests were used to compare differences between groups. RESULTS: Patients and controls had similar age at death (mean 79 yrs) and 61% were female in both groups. Overall, there was no significant difference in grade of stenosis or number of acute coronary lesions. Among subjects with CVD, 54% of controls had grade 3-4 lesions in left main artery versus only 7% of patients (p = 0.023). Vulnerable plaques in left anterior descending (LAD) artery were significantly more common in patients than controls (p = 0.018). Inflammation was observed more frequently in patients, in both the media of left circumflex (p = 0.005) and adventitia of LAD artery (p = 0.024). Similar trends were seen for subjects with heart failure. CONCLUSION: There was less histologic evidence of atherosclerosis but greater evidence of inflammation and instability in RA patients compared to controls. These differences suggest that the mechanisms responsible for cardiovascular morbidity and mortality may be different in patients with RA.

Davis JM, Maradit Kremers H, Crowson CS, Nicola PJ, Ballman KV, Therneau TM, Roger VL, Gabriel SE. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Arthritis Rheum. · Pubmed #17330254 links to  free full text

Abstract: OBJECTIVE: To determine the relationship between glucocorticoid exposure and cardiovascular (CV) events in patients with rheumatoid arthritis (RA). METHODS: A total of 603 adult residents of Rochester, Minnesota with incident RA between 1955 and 1995 were followed up through their medical records for a median of 13 years (total of 9,066 person-years). Glucocorticoid exposure was defined 3 ways: tertiles of cumulative exposure; recent use (< or =3 months) versus past use (>3 months); and average daily dosage (< or =7.5 mg/day or >7.5 mg/day). CV events, including myocardial infarction, heart failure, and death from CV causes, were defined according to validated criteria. Cox regression models were adjusted for demographic features, CV risk factors, and RA characteristics. RESULTS: Rheumatoid factor (RF)-negative patients with exposure to glucocorticoids were not at increased risk of CV events, irrespective of the glucocorticoid dosage or timing of use, as compared with the reference group of RF-negative patients who had never been exposed to glucocorticoids. In contrast, RF-positive patients were at increased risk of CV events, particularly with higher cumulative exposure, higher average daily dosage, and recent use of glucocorticoids. RF-positive patients with high cumulative exposure to glucocorticoids had a 3-fold increased risk of CV events (hazard ratio 3.06 [95% confidence interval 1.81-5.18]), whereas RF-negative patients with high cumulative exposure were not at increased risk (hazard ratio 0.85 [95% confidence interval 0.39-1.87]). CONCLUSION: RF-positive but not RF-negative patients were at increased risk of CV events following exposure to glucocorticoids. These findings suggest that glucocorticoids interact with RF status to modulate the occurrence of CV events in patients with RA. The mechanisms underlying this interaction are unknown and should be the subject of further research.

Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Jacobsen SJ, Roger VL, Gabriel SE. · Department of Health Sciences Research, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA. · Ann Rheum Dis. · Pubmed #16818462 No free full text.

Abstract: BACKGROUND: Inflammatory markers are associated with heart failure. Patients with rheumatoid arthritis have twice the risk of heart failure compared with people without rheumatoid arthritis. OBJECTIVE: To assess whether heart failure in patients with rheumatoid arthritis is preceded by an inflammatory activation as shown by erythrocyte sedimentation rate (ESR), a systemic marker of inflammation. METHODS: A population-based inception cohort of 575 patients with rheumatoid arthritis, free of heart failure at their rheumatoid arthritis incidence date, was followed up longitudinally until death or 2001. During 15 years of follow-up, they had a median of 15 ESR tests, and 172 patients had new-onset heart failure (Framingham Heart Study criteria). The follow-up period, beginning with the rheumatoid arthritis incidence date and ending with date of the last follow-up, was divided into 6-month intervals. The proportions of patients with at least one ESR value >/=40 mm/h and with anaemia (haemoglobin <11 g/dl) within each 6-month interval were plotted against time from fulfilment of heart failure criteria. A binomial test was used to compare proportions. RESULTS: In patients with rheumatoid arthritis who developed heart failure, the proportion with ESR >/=40 mm/h was highest (23%) during the 6-month period immediately preceding the new-onset heart failure, as compared with the average ESR during the entire remaining follow-up period, both before and after heart failure (10.6%; p<0.01). The proportion of patients with anaemia peaked (54%) during the 6-month period after heart failure. CONCLUSIONS: Inflammatory stimuli may be involved in the initiation of heart failure among patients with rheumatoid arthritis.

Nicola PJ, Crowson CS, Maradit-Kremers H, Ballman KV, Roger VL, Jacobsen SJ, Gabriel SE. · Dept. of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. · Arthritis Rheum. · Pubmed #16385496 links to  free full text

Abstract: OBJECTIVE: Although mortality among patients with rheumatoid arthritis (RA) is higher than in the general population, the relative contribution of comorbid diseases to this mortality difference is not known. This study was undertaken to evaluate the contribution of congestive heart failure (CHF) and ischemic heart disease (IHD), including myocardial infarction, to the excess mortality in patients with RA, compared with that in individuals without RA. METHODS: We assembled a population-based inception cohort of individuals living in Rochester, Minnesota, in whom RA (defined according to the criteria of the American College of Rheumatology [formerly, the American Rheumatism Association]) first developed between 1955 and 1995, and an age- and sex-matched non-RA cohort. All subjects were followed up until either death, migration from the county, or until 2001. Detailed information from the complete medical records was collected. Statistical analyses included the person-years method, cumulative incidence, and Cox regression modeling. Attributable risk analysis techniques were used to estimate the number of RA deaths that would be prevented if the incidence of CHF was the same in patients with RA and non-RA subjects. RESULTS: The study population included 603 patients with RA and 603 subjects without RA. During followup, there was an excess of 123 deaths among patients with RA (345 RA deaths occurred, although only 222 such deaths were expected). The mortality rates among patients with RA and non-RA subjects were 39.0 and 29.2 per 1,000 person-years, respectively. There was a significantly higher cumulative incidence of CHF (but not IHD) in patients with RA compared with non-RA subjects (37.1% versus 27.7% at 30 years of followup, respectively; P < 0.001). The risk of death associated with either CHF or IHD was not significantly different between patients with RA and non-RA subjects. If the risk of developing CHF was the same in patients with RA and individuals without RA, the overall mortality rate difference between RA and non-RA hypothetically would be reduced from 9.8 to 8.0 excess deaths per 1,000 person-years; that is, 16 (13%) of the 123 excess deaths could be prevented. CONCLUSION: CHF, rather than IHD, appears to be an important contributor to the excess overall mortality among patients with RA. CHF contributes to this excess mortality primarily through the increased incidence of CHF in RA, rather than increased mortality associated with CHF in patients with RA compared with non-RA subjects. Eliminating the excess risk of CHF in patients with RA could significantly improve their survival.

Maradit-Kremers H, Nicola PJ, Crowson CS, O'Fallon WM, Gabriel SE. · Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. · J Rheumatol. · Pubmed #16358365 No free full text.

Abstract: OBJECTIVE: A major challenge in management of rheumatoid arthritis (RA) is prediction of longterm response to disease-modifying antirheumatic drug (DMARD) treatment. Our objective was to identify the predictors of DMARD discontinuation in an incidence cohort of patients with RA followed continuously from their incidence date. METHODS: Members of a population-based incidence cohort of Rochester, Minnesota, residents aged > or = 18 years diagnosed with RA (by 1987 American College of Rheumatology criteria) from January 1, 1955, to January 1, 1995, were followed longitudinally through their complete medical records until January 1, 2001. Detailed drug exposure data were collected on all DMARD and glucocorticoid regimens. Subjects were considered exposed to a DMARD if duration of use was > or = 30 days. Time to discontinuation of DMARD was estimated using survival analysis techniques. Andersen-Gill models with multiple events per patient were used to assess the influence of demographics, calendar time, comorbidities, disease characteristics [disease duration, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), joint counts, radiographic changes, nodules, RA complications], and therapy characteristics (DMARD use, singly or in combination, glucocorticoid use, first or subsequent regimen, effect of previous therapy) on time from DMARD initiation to discontinuation. RESULTS: The study population comprised 345 DMARD-treated patients (73% female) with mean age of 53.1 years and mean followup 15.4 years. Median time taking any DMARD was 16.0 months for the first, and 17.9 months for all regimens. Methotrexate (MTX) had the longest time to discontinuation, with a median of 30.3 months without folate, and 61.7 months with folate supplementation. Among the various disease characteristics examined, only higher ESR at DMARD initiation was significantly associated with a shorter time taking DMARD [hazard ratio (HR) 1.05 per 10 mm/h increase, 95% CI 1.02, 1.08]. In multivariable Andersen-Gill models considering all DMARD regimens, hydroxychloroquine use (HR 0.77, 95% CI 0.64, 0.92) and MTX use (HR with folate 0.39, 95% CI 0.30, 0.51; HR without folate 0.51, 95% CI 0.39, 0.67) were significantly associated with longer time to DMARD discontinuation, whereas prior MTX use (HR 1.96, 95% CI 1.57, 2.45) was associated with shorter time to DMARD discontinuation, after adjusting for age, sex, calendar year, Charlson comorbidity index, disease duration, and ESR at DMARD initiation. Disease duration was negatively associated with time to DMARD discontinuation; each 10 year increase in disease duration corresponded to a 14% decrease in the risk of discontinuation (HR 0.86, 95% CI 0.75, 0.98). CONCLUSION: Longer RA disease duration does not appear to increase the risk of DMARD discontinuation. However, high disease activity (as assessed by ESR) is associated with a higher likelihood of discontinuing DMARD. MTX failure may identify a subgroup of patients who are less likely to respond to other DMARD and therefore could be considered as candidates for biological therapies.

Crowson CS, Nicola PJ, Kremers HM, O'Fallon WM, Therneau TM, Jacobsen SJ, Roger VL, Ballman KV, Gabriel SE. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Arthritis Rheum. · Pubmed #16200583 links to  free full text

Abstract: OBJECTIVE: To compare the proportion of the risk for the development of heart failure (HF) that is attributable to traditional cardiovascular (CV) risk factors, ischemic heart disease (IHD), and alcohol abuse between subjects with and subjects without rheumatoid arthritis (RA). METHODS: A population-based inception cohort of RA patients was assembled along with a similar cohort of subjects without RA. All individuals were followed up through their complete medical records, until HF incidence, death, migration, or January 1, 2001. The attributable risk of HF was estimated as the difference between the observed cumulative incidence of HF in each cohort (estimated from multivariable Cox models and adjusted for the competing risk of death) and the predicted cumulative incidence of HF in the absence of risk factors, with results expressed as a percentage of the observed cumulative incidence. RESULTS: A total of 575 RA subjects and 583 non-RA subjects (mean age 57 years, 73% women) without HF at incidence/index date had a mean followup of 15.1 and 17.0 years, respectively. During that period, 165 RA and 115 non-RA subjects had a first episode of HF, with a cumulative incidence of 36.3% and 20.4%, respectively, at age 80 years. Among non-RA subjects, 77% of the HF at age 80 years was attributable to CV risk factors, IHD, and alcohol abuse combined, whereas among RA subjects, only 54% of the HF at age 80 years was attributable to these factors (P < 0.01). CONCLUSION: The excess risk of HF among RA patients is not explained by an increased frequency or effect of CV risk factors and IHD.

Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Arthritis Rheum. · Pubmed #15751097 links to  free full text

Abstract: OBJECTIVE: To determine whether systemic inflammation confers any additional risk for cardiovascular death among patients with rheumatoid arthritis (RA), after adjusting for traditional cardiovascular risk factors and comorbidities. METHODS: Using the population-based data resources of the Rochester Epidemiology Project, we assembled an incidence cohort of all Rochester, Minnesota residents ages >or=18 years who first fulfilled the American College of Rheumatology 1987 criteria for RA between January 1, 1955 and January 1, 1995. All subjects were followed up longitudinally through their complete (inpatient, outpatient) medical records, beginning at age 18 years and continuing until death, migration, or January 1, 2001. Detailed information on the occurrence of various cardiovascular risk factors (personal history of coronary heart disease [CHD], congestive heart failure, smoking, hypertension, dyslipidemia, body mass index [BMI], diabetes mellitus, menopausal status) as well as indicators of systemic inflammation and RA disease severity (rheumatoid factor [RF] seropositivity, erythrocyte sedimentation rate [ESR], joint swelling, radiographic changes, RA nodules, RA complications, RA treatments, disease duration) and comorbidities were collected on all subjects. Causes of death were ascertained from death certificates and medical records. Cox regression models were used to estimate the independent predictors of cardiovascular death. RESULTS: This inception cohort comprised a total of 603 RA patients whose mean age was 58 years, of whom 73% were women. During a mean followup of 15 years, 354 patients died and cardiovascular disease was the primary cause of death in 176 patients. Personal history of CHD, smoking, hypertension, low BMI, and diabetes mellitus, as well as comorbidities, including peripheral vascular disease, cerebrovascular disease, chronic pulmonary disease, dementia, ulcers, malignancies, renal disease, liver disease, and history of alcoholism, were all significant risk factors for cardiovascular death (P < 0.01 for each). Multivariable Cox regression analyses, controlled for cardiovascular risk factors and comorbidities, revealed that the risk of cardiovascular death was significantly higher among RA patients with at least 3 ESR values of >or=60 mm/hour (hazard ratio [HR] 2.03, 95% confidence interval [95% CI] 1.45-2.83), RA vasculitis (HR 2.41, 95% CI 1.00-5.81), and RA lung disease (HR 2.32, 95% CI 1.11-4.84). CONCLUSION: These results indicate that markers of systemic inflammation confer a statistically significant additional risk for cardiovascular death among patients with RA, even after controlling for traditional cardiovascular risk factors and comorbidities.

Nicola PJ, Maradit-Kremers H, Roger VL, Jacobsen SJ, Crowson CS, Ballman KV, Gabriel SE. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Arthritis Rheum. · Pubmed #15692992 links to  free full text

Abstract: OBJECTIVE: It is hypothesized that the systemic inflammation associated with rheumatoid arthritis (RA) promotes an increased risk of cardiovascular (CV) morbidity and mortality. We examined the risk and determinants of congestive heart failure (CHF) in patients with RA. METHODS: We assembled a population-based, retrospective incidence cohort from among all individuals living in Rochester, Minnesota, in whom RA (defined according to the American College of Rheumatology 1987 criteria) was first diagnosed between 1955 and 1995, and an age- and sex-matched non-RA cohort. After excluding patients in whom CHF occurred before the RA index date, all subjects were followed up until either death, incident CHF (defined according to the Framingham Heart Study criteria), migration from the county, or until January 1, 2001. Detailed information from the complete medical records (including all inpatient and outpatient care provided by all local providers) regarding RA, ischemic heart disease, and traditional CV risk factors was collected. Cox models were used to estimate the effect of RA on the development of CHF, adjusting for CV risk factors and/or ischemic heart disease. RESULTS: The study population included 575 patients with RA and 583 subjects without RA. The CHF incidence rates were 1.99 and 1.16 cases per 100 person-years in patients with RA and in non-RA subjects, respectively (rate ratio 1.7, 95% confidence interval [95% CI] 1.3-2.1). After 30 years of followup, the cumulative incidence of CHF was 34.0% in patients with RA and 25.2% in non-RA subjects (P< 0.001). RA conferred a significant excess risk of CHF (hazard ratio [HR] 1.87, 95% CI 1.47-2.39) after adjusting for demographics, ischemic heart disease, and CV risk factors. The risk was higher among patients with RA who were rheumatoid factor (RF) positive (HR 2.59, 95% CI 1.95-3.43) than among those who were RF negative (HR 1.28, 95% CI 0.93-1.78). CONCLUSION: Compared with persons without RA, patients with RA have twice the risk of developing CHF. This excess risk is not explained by traditional CV risk factors and/or clinical ischemic heart disease.